Focus On: Neuroscience and Treatment

The Potential of Neuroscience
to Inform Treatment

George F. Koob, Ph.D.

GEORGE F. KOOB,
PH.D., is a professor and chair of the Committee on the Neurobiology of Addictive
Disorders at the Scripps Research Institute and adjunct professor in the Departments
of Psychology and Psychiatry, and adjunct professor in the Skaggs School of Pharmacy
and Pharmaceutical Sciences at the University of California, San Diego, San Diego,
California.

In the 40 years since the founding of the National
Institute on Alcohol Abuse and Alcoholism (NIAAA), researchers have gained a better
understanding of the brain circuits and brain chemical (i.e., neurotransmitter)
systems involved in the development and maintenance of alcoholism and other drug
dependence. This understanding has led to the identification of numerous potential
targets for pharmacotherapy of addiction. For example, insight into the roles
of signaling molecules called endogenous opioids and the neurotransmitter glutamate
were fundamental for developing two medications—naltrexone and acamprosate—now
used in the treatment of alcoholism. However, the processes of dependence development
(e.g., reinforcement, sensitization, and withdrawal) are highly complex and involve
a plethora of contributing influences, which also may differ from patient to patient.
Therefore, existing pharmacotherapies still are effective only for some but not
all alcoholic patients. Accordingly, researchers are continuing to explore the
processes involved in addiction development to identify new targets for treatment
and develop new medications that can address different aspects of the dependence
syndrome, thereby increasing the likelihood of successful treatment. NIAAA continues
to play a pivotal role in funding and conducting this research in order to provide
effective treatment options to millions of alcohol-dependent patients. Key
words: Alcohol and other drug dependence; alcoholism; brain; brain circuit; brain
chemistry; neurotransmitters; treatment; pharmacotherapy; medications

Alcoholism,
like addiction to other drugs, is a chronic, relapsing disorder characterized
by compulsive alcohol use that is thought to include three stages (Koob and Le
Moal 1997). These stages have heuristic value as a construct because they are
components of the addiction process in general (i.e., have face validity), and
they have value in predicting not only the neurobiological bases of addiction
but also medications for the treatment of addiction (i.e., have construct validity)
(Koob et al. 2009). The three stages include the following:

The
binge–intoxication stage, during which a downregulation of positive reward
pathways occurs—that is, increasing drug levels are needed to trigger the
brain reward system. During this stage, alcohol and other drug (AOD) use is motivated
primarily by positive rewarding experiences.

The withdrawal–negative-affect
stage, during which the drug user transitions to AOD addiction and experiences
negative consequences (i.e., withdrawal symptoms) when AOD use is discontinued.
At this stage, AOD use begins to be motivated primarily by the desire to avoid
negative experiences (i.e., by negative reinforcement).

The preoccupation–anticipation
(“craving”) stage, which is characterized by exaggerated motivation
for drug use (i.e., craving).

All three stages are associated
with specific changes in the structure and function of various brain-signaling
molecule (i.e., neurotransmitter) systems and in the circuits connecting various
brain regions to relay information related to a specific function. As a result
of these neurochemical and neurocircuitry changes, the person eventually loses
behavioral control over drug seeking and drug taking. Because neurotransmitters
and the circuits they act on are pivotal players in the development of alcohol
dependence and other addictions, they also are prime targets for pharmacotherapies
for these disorders. Accordingly, over the past 40 years, the National Institute
on Alcohol Abuse and Alcoholism (NIAAA) has strongly supported research into the
neurochemical mechanisms underlying the development of various aspects of addiction,
such as positive and negative reinforcement, development of tolerance, sensitization
to alcohol’s effects, and development of withdrawal symptoms after cessation
of drinking. Other research has focused on the brain circuits that are altered
by repeated exposure to alcohol and on the development of animal and human laboratory
models that reflect various aspects of addiction. This comprehensive approach
led to the development of the drug naltrexone (Revia®, Depade®),
which acts at one type of neurotransmitter receptor affected by alcohol (i.e.,
opioid receptors). Naltrexone was approved for the treatment of alcohol dependence
based on two NIAAA-supported clinical trials (O’Malley et al. 1992; Volpicelli
et al. 1992). NIAAA continues supporting the identification of new targets for
pharmacotherapy interventions, development of candidate compounds, and testing
of these compounds in validated preclinical models and clinical studies. This
article reviews some of the neurobiological targets currently studied for the
development of new treatment approaches for alcoholism and other drug addictions
and their proposed actions during the various stages of AOD addiction.

NEUROBIOLOGICAL
TARGETS IN THE TREATMENT OF ADDICTION

For researchers to select appropriate
targets for novel pharmacotherapeutic approaches, they must first gain an understanding
of the neurobiology of addiction—that is, of the brain circuits and signaling
systems involved in the various stages of addiction. Several neurobiological circuits
have been identified, each of which are central to one or more of the three stages
of addiction (Koob and Le Moal 2006) and which may be promising targets for potential
pharmacotherapy (see the figure):

Figure.
Neurocircuitry schematic illustrating the combination of neuroadaptations in the
brain circuitry for the three stages of the addiction cycle that drive drug-seeking
behavior in the addicted state. Note the activation of the ventral striatum/dorsal
striatum in the binge intoxication stage. During the withdrawal–negative-affect
stage, the dopamine systems are compromised and brain stress systems such as CRF
are activated to reset further the salience of drugs and drug-related stimuli
in the context of an aversive dysphoric state. During the preoccupation–anticipation
stage, contextual cues via the hippocampus and stimuli cues via the basolateral
amygdala converge with frontal cortex activity to drive drug seeking. Other components
in the frontal cortex are compromised, producing deficits in executive function.

SOURCE: Koob et al. 2008.

The mesocorticolimbic
dopamine system and its terminal areas in the ventral striatum, which includes
signaling by the neurotransmitter dopamine and signaling molecules called opioid
peptides, is involved in mediating the positive reinforcing drug effects associated
with the binge–intoxication stage of the addiction cycle (Nestler 2005).

The body’s stress response system—known as the hypothalamic–pituitary–adrenal
(HPA) stress response—and the brain’s stress response become activated
during the withdrawal–negative-affect stage (Koob 2008). At the same time,
neuronal systems implicated in the positive reinforcing effects of AODs are disrupted
(e.g., dopamine activity decreases). Both body and brain stress responses involve
a molecule called corticotropin-releasing factor (CRF); in the HPA response, CRF
acts in the hypothalamus or pituitory, whereas for the brain’s stress response
CRF acts outside the hypothalamus on the pituitary (i.e., extrahypothalamic) in
a region called the amydala. With repeated cycles of drinking and withdrawal,
the HPA response becomes weaker (i.e., blunted), whereas the extrahypothalamic
CRF stress system becomes more sensitive (Koob 2008).

The delineation of
these circuits and the signaling molecules involved has allowed, and will continue
to allow, researchers to identify appropriate targets for additional therapeutic
interventions, develop medications that act on these targets, and test these medications
in validated animal models and, if there is evidence of effectiveness, in human
clinical trials.

NEW TARGETS FOR MEDICATION DEVELOPMENT

Three key
sources can provide information for the development of new medications: research
into basic neurobiological mechanisms underlying the different stages of the addiction
cycle, the effects of currently approved medications on animal models of the different
stages of the addiction cycle, and clinical studies of medications approved for
other indications that overlap with specific components of addiction. Information
from these sources has led to investigations of a variety of neurotransmitter
systems affecting different aspects of the dependence syndrome. The emphasis of
this discussion is on neuronal circuits and neurotransmitter systems involved
in the withdrawal–negative-affect stage of addiction, because the fear of
experiencing withdrawal symptoms (which are caused by the brain’s adaptation
to the continued presence of alcohol) is one motivation for alcoholics to continue
drinking (Koob and Le Moal 2008), and, even more importantly, negative emotional
states during protracted abstinence provide a strong motivation for relapse. These
neurotransmitter systems involved include the dopamine, g-aminobutyric acid (GABA),
CRF, and glutamate systems, all of which target circuits that can restore deregulated
reward systems involved during the withdrawal–negative-affect stage. Moreover,
dopamine can affect the binge–intoxication stage and glutamate acts during
the preoccupation–anticipation stage. Some of these neurotransmitter systems
(i.e., GABA, glutamate, and CRF) already are targets of medications used to treat
addiction, but all of them still have the potential to yield new medications (see
table). (Koob et al. 2009).

Table. Neurotransmitter Systems in the Brain Involved
in Different Stages of the Addiction Cycle and Existing and Potential Pharmacotherapies
Targeting Them in the Treatment of Alcohol Dependence

Agents Acting on the Dopamine System

The mesolimbic
dopamine system projects from the ventral tegmental area (VTA) to basal forebrain
sites, the NAc, and the central nucleus of the amygdala; it has a key role in
motivation and mediates the reinforcing actions of many drugs of abuse, including
alcohol. Moreover, normal functioning of this system is disrupted during acute
withdrawal from all major drugs of abuse (Weiss and Koob 2001). For example, dopamine
levels in the NAc decrease substantially in animals undergoing withdrawal from
alcohol (Weiss et al. 1996). Moreover, dopamine-releasing neurons in the VTA show
decreased activity during withdrawal from most major drugs of abuse (Melis et
al. 2005). Therefore, it appears plausible that medications altering dopamine
activity could be effective in the treatment of AOD addiction.

Researchers
have studied the effects of dopamine partial agonists1 [1To
exert its effects, dopamine (like any other neurotransmitter) is released by a
signal-emitting nerve cell (i.e., neuron) and interacts with docking molecules
(i.e., receptors) on the surface of the signal-receiving neuron. This interaction
induces a chain of reactions in the signal-receiving cell, resulting either in
the generation or suppression of a new nerve signal, depending on the neurotransmitter
and cells involved. Agents that bind to a neurotransmitter receptor and induce
the same response as the normal neurotransmitter are called agonists; agents that
bind to the receptor, thereby blocking the normal neurotransmitter or an agonist
from binding and preventing receptor activation, are called antagonists.]—agents
that block the activities of the dopamine receptors (i.e., act as dopamine antagonists)
when normal dopamine activity is high but enhance receptor activity (i.e., act
as agonists) when dopamine activity is low. Such an approach is thought to generate
less severe or fewer side effects than full agonists or antagonists (Pulvirenti
and Koob 2002). The validity of this approach has been demonstrated by findings
that partial agonists of one of the dopamine receptors (i.e., the D2
receptor) decreased the reinforcing effects of orally self-administered alcohol
in nondependent2 [2The term nondependent refers to animals
with limited access to alcohol that do not show physical or motivational symptoms
of withdrawal when alcohol is removed. Conversely, dependent rats had, with sufficient
exposure to alcohol, to show physical or motivational symptoms of withdrawal when
alcohol is removed.] rats (Bono et al. 1996). Studies using animals that self-administered
psychostimulants (e.g., amphetamine) found that D2 partial agonists
can reverse some of the effects of withdrawal (e.g., Orsini et al. 2001), but
the approach using partial agonists has yet to be explored in animal models of
compulsive drinking.

Other agents targeting the dopamine system also have
shown effectiveness in preventing some aspects of alcohol dependence. For example,
antagonists of the dopamine D3 receptor have blocked cue-induced reinstatement
of cocaine and alcohol self-administration (Heidbreder et al. 2005), and other
investigators are studying the effects of D1 receptor antagonists on
various aspects of drug dependence. Together, the results obtained to date suggest
that altered dopamine signaling contributes to craving for and relapse to AOD
use and that therefore dopamine partial agonists may be effective in treating
certain aspects of addiction (Spanagel and Kiefer 2008).

Agents Acting
on the GABA System

GABA also acts at several different receptors (i.e.,
GABAA and GABAB receptors) that have been studied as targets
for medications to treat alcoholism and other addictions. For example, GABAA
receptor antagonists and inverse agonists3 [3Inverse
agonists bind to the same receptor as a normal neurotransmitter or agonist but
induce the opposite effect (rather than just preventing neurotransmitter or agonist
actions by blocking their interaction with the receptor).] decrease alcohol self-administration
in animals (Hyytia and Koob 1995; Rassnick et al. 1993). However, these agents
cause excessive excitability of certain brain cells, limiting their usefulness.
In contrast, GABA receptor agonists or agents that modulate receptor activity
can block drug-seeking behavior by acting on a variety of brain systems. For example,
in nondependent rats, GABA receptor modulators that increased GABAergic activity
reduced the animal’s self-administration of alcohol (Colombo et al. 2003).
GABA receptor agonists also block alcohol withdrawal in animals (Frye et al. 1983)
and decrease drinking and certain components of craving in alcoholics (Addolorato
et al. 2002a,b). The GABAB agonist baclofen even
has been reported to reduce alcohol craving and intake in a preliminary double-blind,
placebo-controlled trial (Addolorato et al. 2002a). However, these agents
have substantial sedative effects at therapeutic doses, limiting their usefulness.
To circumvent this, researchers are studying GABA receptor modulators that act
more indirectly.

One of these is gabapentin (Neurontin®;
Pfizer), a molecule designed to have a similar structure as GABA that mainly interacts
with voltage-gated N-type calcium channels (Sills 2006). It originally was developed
as an anticonvulsant drug, but because it increases GABA concentrations in the
brain (Taylor et al. 1998), it also has been evaluated for alcohol dependence.
In animal studies, gabapentin had strikingly different effects in nondependent
and alcohol-dependent rats (Roberto et al. 2008). In nondependent rats, it facilitated
GABAergic transmission in the central nucleus of the amygdala but did not affect
alcohol intake. In dependent rats, however, gabapentin decreased both GABAergic
transmission and alcohol intake. These findings suggest that during the development
of alcohol dependence, neuroadaptive changes occur in the GABA system, including
a reduction in sensitivity and/or number of the GABAB receptors (Roberto
et al. 2008). Moreover, in human laboratory studies, gabapentin decreased craving
and reversed or ameliorated some of the consequences of protracted abstinence
(Mason et al. 2009). These findings provide a prime example for how analyses of
neurobiological processes associated with dependence can lead to testing of novel
agents (or agents that were developed for a different purpose) in animal models
and, subsequently, humans, potentially resulting in new treatment approaches.

Agents Acting on the Brain Stress System

Agents
Acting on the CRF System. Alcohol is a powerful activator of stress
systems involving both the HPA axis and extrahypothalamic CRF systems in the extended
amygdala; the latter also become hyperactive during withdrawal, leading to increased
CRF levels in certain brain regions (i.e., the central nucleus of the amygdala
and the bed nucleus of the stria terminalis) (Funk et al. 2006; Merlo-Pich et
al. 1995; Olive et al. 2002). In animal models, acute withdrawal and protracted
abstinence from alcohol and all other major drugs of abuse produce anxiety-like
responses that are mediated by CRF and can be reversed by CRF receptor antagonists
(Knapp et al. 2004; Overstreet et al. 2004). The effects of these antagonists
also appear to be specific to alcohol-dependent animals. Thus, an antagonist that
acts at different CRF receptors had no effect on alcohol self-administration in
nondependent rats but eliminated excessive drinking in dependent rats during acute
withdrawal and protracted abstinence (Valdez et al. 2002). Similarly, injections
of other CRF antagonists blocked increased alcohol intake during acute withdrawal
and protracted abstinence in alcohol-dependent rats but not in nondependent rats
(Funk et al. 2007; Gehlert et al. 2007). These data suggest that extrahypothalamic
CRF is an important mediator in the increased self-administration associated with
alcohol dependence and therefore a promising target for pharmacotherapy. However,
no human laboratory studies or clinical trials have yet been initiated to investigate
the effects of CRF antagonists on alcohol dependence.

Agents
Acting on Non-CRF Brain Stress Targets. Other neurotransmitter systems
and neuromodulators within the stress systems of the extended amygdala also may
be deregulated during the development of AOD dependence. Thus, deregulation of
noradrenaline, dynorphin, vasopressin, orexin, and substance P all appear to play
a role in alcohol dependence (Koob 2008). Accordingly, these signaling systems
also may be appropriate targets for pharmacotherapy. For example, administration
of an antagonist acting at one of the noradrenergic receptors decreases self-administration
in alcohol-dependent rats (Walker et al. 2008). Noradrenaline also interacts with
CRF during the brain stress activation associated with withdrawal from AODs (Koob
2008).

Dynorphins are a class of endogenous opioids that interact with the
κ-opioid receptor and are thought to mediate negative emotional states. Accordingly,
κ-opioid receptor agonists produce depression and dysphoria in humans (Pfeiffer
et al. 1986). Furthermore, κ-opioid receptors have been linked to reinstatement
of drug-seeking behavior because in alcohol-dependent rats, a κ-opioid receptor
antagonist selectively blocked the increase in alcohol self-administration associated
with withdrawal (Walker and Koob 2008). Therefore, the dynorphin system may provide
another avenue to treating alcohol dependence. This approach already has been
tested successfully in models of addiction to other drugs and clearly warrants
study in models of alcohol dependence.

Finally, some neuromodulatory systems
that counteract CRF in the brain stress response are being investigated as potential
targets for pharmacotherapy of alcohol dependence. These include, for example,
signaling systems using molecules called neuropeptide Y, nociceptin, and substance
P. Agonists of the neuropeptide Y and nociceptin systems have been shown to reduce
excessive drinking associated with alcohol dependence (Ciccocioppo et al. 2000;
Heilig et al. 1994). Conversely, approaches to reduce the activity of the receptor
system for substance P reduced voluntary drinking in high-alcohol–consuming
mice and reduced craving and other physiological responses in recently detoxified
alcoholic patients (George et al. 2008).

Taken together, all of these findings
suggest that agents which interfere with various CRF-mediated and non-CRF–mediated
responses of the brain stress system to alcohol might have potential as new treatment
approaches for alcoholism and should be investigated further. Continued support
with funding from NIAAA and other sources will be essential for the translation
of laboratory findings in animals and humans into treatments for large numbers
of alcoholic patients. Particularly critical at this juncture is the continued
cross-validation of animal and human laboratory models that are predicative of
treatment efficacy.

Agents Acting on the Glutamate System

The
neurotransmitter glutamate interacts with several receptors, including the N-methyl-D-aspartate
(NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainate,
and metabotropic glutamate receptors. The glutamate system acts at several sites
in the neurobiology of alcohol dependence, many of which provide potential targets
for medications development. For example, at low doses alcohol acts as an NMDA
receptor antagonist, and this reduction of glutamatergic activity may mediate
the acute rewarding effects of alcohol (Hoffman et al. 1989). Conversely, the
glutamatergic system shows excessive activity during acute and prolonged abstinence
from alcohol. Analyses of these effects of alcohol consumption and withdrawal
on the glutamate system have led to the development of the medication acamprosate,
which is a partial agonist of the NMDA receptor and an antagonist of metabotropic
glutamate receptors (de Witte et al. 2005; Spanagel and Kiefer 2008).

AMPA
or kainate receptors also appear to mediate some of glutamate’s effects
in addiction processes, as indicated by the results of clinical trials with the
anticonvulsant medication topiramate. This agent acts as an antagonist at AMPA
and kainate receptors but not NMDA receptors. In animal models of alcoholism,
topiramate decreased alcohol consumption and preference but failed to block place
preference to alcohol in mice (Gabriel and Cunningham 2005; Gremel et al. 2006).
Topiramate did block stress-induced increases in alcohol consumption and preference
(Farook et al. 2009) and conditioned abstinence behavior in mice (Farook et al.
2007). These and other findings suggest that topiramate may act on brain stress
systems to reduce the motivation for alcohol seeking in dependence. In clinical
trials involving alcohol-dependent patients, topiramate reduced drinking behavior
and improved the participants’ quality of life (Johnson et al. 2007; Olmsted
and Kockler 2008). However, this treatment also produced significant adverse effects
on memory and concentration.

Because direct glutamatergic antagonists can
induce significant side effects, medications that modulate the system may be more
promising candidates for the treatment of addiction, including alcoholism. Such
agents may not only be able to dampen the hyperexcitability of glutamatergic systems
during protracted abstinence from alcohol but also may decrease drug- and cue-induced
reinstatement of alcohol self-administration. For example, both an antagonist
of metabotropic glutamate receptor 5 (mGluR5) and agonists of mGluR2 and mGluR3,
all of which decrease glutamate function, blocked cue-induced reinstatement of
alcohol self-administration (Schroeder et al. 2008; Zhao et al. 2006).

CONCLUSIONS
AND FUTURE DIRECTIONS

The U.S. National Institutes of Health, and particularly
NIAAA, has supported much of the research into the mechanisms underlying the development
of alcohol dependence, thereby laying the foundation for the development of effective
pharmacotherapies for this debilitating disorder. This NIAAA-funded research has
led to tremendous breakthroughs in elucidating the basic neurobiology of addiction
and in developing and validating behavioral and pharmacological treatments of
alcoholism. For example, preclinical and clinical proof-of-concept in the development
of naltrexone for the treatment of alcoholism would not have been possible without
NIAAA funding.

However, none of the existing medications are effective in
all patients, and additional agents need to be identified and developed that allow
for effective treatment of additional patient subgroups. As described here, analyses
of the neurobiology underlying both the withdrawal–negative-affect stage
and the preoccupation–anticipation (craving) stage of the addiction cycle
already have revealed numerous potential new targets for pharmacotherapy development.
In fact, agents that act on neurotransmitter systems associated with both of these
stages would be optimal.

Thus, there is substantial potential for the development
of future pharmacotherapies for treatment of addiction. Moreover, further analyses
of currently available medications in validated animal models can yield additional
information on the neuronal circuits and neuropharmacological mechanisms involved
in the development and maintenance of addiction, thereby providing a means to
identify additional targets and to develop and evaluate future medications.

Animal
models can be defined as experimental paradigms developed for the purpose of studying
a given phenomenon found in humans, and animal models remain key elements for
exploring the neurobiological bases of psychiatric disorders and providing targets
for medications development. However, animal models for a complete syndrome of
a psychiatric disorder are unlikely to be possible either conceptually or practically.
Thus, although there are no complete animal models of psychiatric disorders, animal
models do exist for individual elements of each syndrome. One approach to the
development of animals models of heuristic value is that animal models are most
likely to have construct validity when the model mimics only the specific signs
or symptoms associated with a pathological condition (Geyer and Markou 1995).
Using this conceptual approach, new procedures in animal models and human laboratory
models in alcoholism are being refined in the context of the three stages of the
addiction cycle outlined above. New data provide compelling evidence for a process
termed the “Rosetta Stone” approach, in which existing pharmacotherapies
are used to validate and improve animal models and human laboratory models, resulting
in improved translation to human clinical therapeutics (Koob et al. 2009). Using
this approach, animal models in the substance use disorders domains have excellent
face and construct validity and have led to major insights into their neurobiological
mechanisms of action. Such information not only provides a rich substrate for
targets for pharmcotherapeutic approaches but also provides an excellent heuristic
basis for validating the efficacy of behavioral approaches to treatment of alcoholism.

Other
efforts could focus on molecular changes that occur in response to alcohol exposure
at the level of signal transduction within or between cells or in the genes encoding
the involved molecules. Such basic research can provide insights into how the
neuronal circuits described in this article become deregulated during the different
stages of the addiction cycle, thereby providing new potential targets for medication
development. Moreover, such effects may identify targets for genetic pharmacology
in which treatments could be individualized for patients based on specific genetic
polymorphisms carried by the individual. To date, no medication targets have been
identified using analyses of such molecular changes but eventually, molecular
studies may become key to understanding the vulnerability to addiction as well
as help identify possible targets for pharmacotherapeutic approaches.

Gremel, C.M.; Gabriel, K.I.; and Cunningham, C.L. Topiramate
does not affect the acquisition or expression of ethanol conditioned place preference
in DBA/2J or C57BL/6J mice. Alcoholism: Clinical and Experimental Research
30:783–790, 2006. PMID:
16634846